Dual role of proapoptotic BAD in insulin secretion and beta cell survival
Dual role of proapoptotic BAD in insulin secretion and beta cell survival
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DOI：
10.1038/nm1717
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发表时间：
2008-02-01
期刊：
影响因子：
82.9
通讯作者：
Korsmeyer, Stanley J.
中科院分区：
文献类型：
--
作者：
Danial, Nika N.;Walensky, Loren D.;Korsmeyer, Stanley J.
促凋亡的BCL - 2家族成员BAD存在于一个含葡萄糖激酶的复合物中，该复合物调节葡萄糖驱动的线粒体呼吸。在此，我们提供了BAD在β细胞的葡萄糖刺激的胰岛素分泌中具有生理作用的遗传学证据。BAD的这一新功能特别依赖于其BH3序列的磷酸化，该BH3序列先前被定义为一个关键的死亡结构域。我们通过使用可穿透细胞的、碳氢化合物固定的BAD BH3螺旋来强调磷酸化BAD BH3的药理学相关性，这些螺旋靶向葡萄糖激酶，恢复葡萄糖驱动的线粒体呼吸，并纠正Bad缺陷胰岛中的胰岛素分泌反应。我们的研究揭示了BAD BH3结构域的一个替代靶点和功能，并强调了磷酸化BAD BH3模拟物在选择性恢复β细胞功能方面的治疗潜力。此外，我们表明BAD在高脂肪喂养期间调节β细胞量的生理适应性。我们的发现为BAD在β细胞存活和胰岛素分泌方面的双功能活性提供了遗传学证据。
The proapoptotic BCL-2 family member BAD resides in a glucokinase-containing complex that regulates glucose-driven mitochondrial respiration. Here, we present genetic evidence of a physiologic role for BAD in glucose- stimulated insulin secretion by beta cells. This novel function of BAD is specifically dependent upon the phosphorylation of its BH3 sequence, previously defined as an essential death domain. We highlight the pharmacologic relevance of phosphorylated BAD BH3 by using cell-permeable, hydrocarbon-stapled BAD BH3 helices that target glucokinase, restore glucose- driven mitochondrial respiration and correct the insulin secretory response in Bad-deficient islets. Our studies uncover an alternative target and function for the BAD BH3 domain and emphasize the therapeutic potential of phosphorylated BAD BH3 mimetics in selectively restoring beta cell function. Furthermore, we show that BAD regulates the physiologic adaptation of beta cell mass during high-fat feeding. Our findings provide genetic proof of the bifunctional activities of BAD in both beta cell survival and insulin secretion.